2-(Substituted amino)-3-nitro-2,3-unsaturated nitrogen heterocycles

ABSTRACT

2,3-Unsaturated nitrogen-containing heterocyclic compounds with a 3-nitro group and a 2-heterocyclyl alkylamino group. The alkyl group of 2-position substituents is preferably interrupted by sulfur or oxygen. The compounds of the invention are preferably dihydropyrroles or tetrahydropyridines or pyrimidines. The compounds of the invention are histamine H 2  -receptor antagonists.

This invention relates to nitro compounds having activity as histamineH₂ -receptor antagonists, pharmaceutical compositions containing themand methods of inhibiting histamine H₂ -receptors by administering thesecompounds.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and it has multiple biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines", of which mepyramine, diphenhydramine andchloropheniramine are typical examples, are mediated through histamineH₁ -receptors. However, others of the biological actions of histamineare not inhibited by "antihistamines", and actions of this type whichare inhibited by burimamide are mediated through receptors which aretermed histamine H₂ -receptors, and H₂ -receptors are defined as thosehistamine receptors which are not blocked by mepyramine but are blockedby burimamide. Compounds which block histamine H₂ -receptors arereferred to as histamine H₂ -receptor antagonists.

Blockade of histamine H₂ -receptors is of value in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines". Histamine H₂ -receptor antagonists are thereforeuseful, for example, as inhibitors of gastric acid secretion, asanti-inflammatory agents, and as agents which act on the cardiovascularsystem, for example as inhibitors of the effects of histamine on bloodpressure.

The compounds of this invention are represented by Structure 1: ##STR1##in which Het is either a 5- or 6-membered, fully-unsaturated heterocyclecontaining at least one nitrogen atom and optionally substituted bylower alkyl, trifluoromethyl, hydroxymethyl, halogen, hydroxy, loweralkoxy or amino, or a 5- membered fully-unsaturated heterocyclecontaining one oxygen or sulfur atom as the sole heteroatom, i.e. furylor thienyl, and substituted by a group R¹ R² N-A- where R¹ and R², whichcan be the same or different, are each hydrogen, lower alkyl, C₃ -C₆cycloalkyl, lower alkenyl, aryl lower alkyl, lower alkyl substituted bylower alkoxy, (lower alkyl)amino or di(lower alkyl)amino, or R¹ and R²together with the nitrogen atom to which they are attached form apyrrolidino or piperidine ring, and A is straight or branched C₁ -C₆alkanediyl group;

Z is sulphur, methylene or oxygen;

m is 0, 1 or 2 and n is 2 or 3 provided that m+n is 3 or 4; and B is a1,2-ethanediyl (--CH₂ --CH₂ --), 1,3-propanediyl (--CH₂ CH₂ CH₂ --) or1,4-butanediyl (--CH₂ CH₂ CH₂ --CH₂) group, which group is optionallysubstituted with one or more lower alkyl, aryl, aryl lower alkyl orheteroaryl lower alkyl groups, or B is a 2-aza-1,3-propanediyl group(--CH₂ NR³ CH₂ -- where R³ is lower alkyl, aryl, aryl lower alkyl orheteroaryl lower alkyl). The compounds of Structure 1 can be in the formof free bases or pharmaceutically acceptable acid addition saltsthereof.

Herein, `lower alkyl` and `lower alkoxy` are used respectively to meanalkyl and alkoxy groups having 1 to 4 carbon atoms which can be straightor branched, and `lower alkenyl` is used to mean alkenyl groupscontaining from 3 to 6 carbon atoms which can be straight or branched.

Examples of nitrogen-containing heterocycles for the group Het areimidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole,1,2,4-triazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole. The group(CH₂)_(m) is preferably linked to a carbon atom of the heterocycleadjacent to a nitrogen atom. The heterocycle of Het is preferablyimidazole. In particular, Het can be 2- or 4-imidazolyl optionallysubstituted by lower alkyl (especially methyl), halogen (especiallychlorine or bromine), trifluoromethyl or hydroxymethyl. Other suitablegroups Het are 2-pyridyl optionally substituted by lower alkyl(especially methyl), lower alkoxy (especially methoxy), halogen(especially chlorine or bromine), amino or hydroxy; 2-thiazolyl;3-isothiazolyl optionally substituted by chlorine or bromine;3-(1,2,5-thiadiazolyl optionally substituted by chlorine or bromine; and2-(5-amino-1,3,4-thiadiazolyl). Specific examples of groups Het are5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-bromo-2-pyridyl,3-chloro-2-pyridyl, 3-methoxy-2-pyridyl and 3-hydroxy-2-pyridyl.

When Het is a 5- membered heterocycle containing one oxygen as the soleheteroatom(furyl), the group (CH₂)_(m) is preferably linked to a carbonatom of the heterocycle adjacent to the oxygen atom. The group R¹ R²N-A- is preferably linked to the other carbon atom of the heterocycleadjacent to the hetero atom. R¹ and R² are preferably hydrogen, loweralkyl (especially methyl), phenyl(lower alkyl) where the phenyl group isoptionally substituted by lower alkyl, lower alkoxy, halogen or di(loweralkyl)amino-(lower alkyl). A is preferably an α,ω-straight alkylenegroup containing from 1 to 3 carbon atoms, particularly methylene.Specific examples of such groups Het are5-(4-dimethylamino)butyl)-2-furyl, 5-((dimethylamino)methyl)-2-furyl and5-(methylaminomethyl)-2-furyl. Preferably Z is sulphur. Preferably m is1 and n is 2.

Each carbon atom of B is preferably secondary or tertiary. The carbonatom of B adjacent to the ring nitrogen atom shown in Structure 1 ispreferably unsubstituted. Examples of aryl substituents and the arylmoiety of aryl lower alkyl substituents for B are phenyl optionallysubstituted with one or more lower alkyl, lower alkoxy or halogengroups, particularly 3-methylphenyl, 3-methoxyphenyl,3,4-dimethoxyphenyl and 3-chlorophenyl, 5- or 6-(2,3-dihydro-1,4-benzodioxinyl) and 4- or 5- (1,3-benzodioxolyl).Examples of heteroaryl substituents for B are 2-furyl, 2-thienyl,2-pyridyl, 3-pyridyl or 4-pyridyl, which groups are optionallysubstituted by one or more lower alkyl or lower alkoxy groups, andparticularly 3-pyridyl, 6-methyl-3-pyridyl and 6-methoxy-3-pyridyl.

Examples of specific compounds of the invention are:

2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-1,4,5,6-tetrahydropyridine,

2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrroleand

4[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-nitro-1-benzyl-1,2,3,6-tetrahydropyrimidine.

The compounds of Structure 1 can be prepared by reacting a compound offormula Het-(CH₂)_(m) Y where Y is --Z(CH₂)_(n) NH₂ or optionally when mis 1 or 2 a leaving group displaceable by a mercaptan, for examplehalogen, trisubstituted phosphonium (for example triphenylphosphonium)or substituted sulphonyloxy (for example p-toluenesulphonyloxy,methanesulphonyloxy or trifluoromethanesulphonyloxy) with a compound ofStructure 2: ##STR2## where X is halogen, QO- or QS (where Q is loweralkyl, aryl or arylalkyl, or another leaving group which is displaceableby an amine) when Y is --Z(CH₂)_(n) NH₂, and X is HS(CH₂)_(n) NH-- whenY is a leaving group displaceable by a mercaptan. This reaction ispreferably carried out in the presence of a solvent, for example a loweralkanol or pyridine. In general an elevated temperature will be used,for example the boiling point of the reaction mixture. The reaction canalso be carried out in the absence of a solvent. X is preferably QS, inparticular methylthio or benzylthio. It will be appreciated that when R¹and/or R² are hydrogen or are lower alkyl substituted by (loweralkyl)amino it may be necessary to protect amino groups in the R¹ R²N-A-substituents of compounds of formula Het-(CH₂)_(m) Y to preventcompeting side reactions.

The intermediate compounds of Structure 2 where X is QS-, and B issubstituted or unsubstituted 1,2-ethanediyl, 1,3-propanediyl or1,4-butanediyl group can be prepared by the following sequence ofreactions. A compound of Structure 3 ##STR3## where X¹ is QS- or QSO-,is reacted with a compound of formula H₂ N-B-Hal, where Hal is chlorine,bromine or iodine to give a compound of Structure 4. This reaction ispreferably carried out in a solvent, for example a lower alkanol.Preferably Hal is bromine or iodine. The compounds of Structure 4 can beconverted into a compound of Structure 5 by reaction with a strong base,for example sodium hydride or potassium t-butoxide. This reaction ispreferably carried out in an inert polar solvent, for exampletetrahydrofuran or dimethylformamide. In general an elevated temperaturewill be used, for example the boiling point of the reaction mixture.

An alternative method for preparing the intermediate compounds ofStructure 2 where X is QS- and B is 1,2-ethanediyl or 1,3-propanediyl isto react a compound of Structure 3 with aziridine or azetidine or a C-substituted derivative thereof to give a compound of Structure 6##STR4## and to heat this compound in the presence of a catalyst, forexample potassium iodide, to give a compound of Structure 5. The latterreaction is preferably carried out in a dry aprotic polar solvent, forexample acetone or 2-butanone.

The intermediate compounds of Structure 2 where X is QS and B is2-aza-1,3-propanediyl can be prepared by reacting a compound ofStructure 7 with formaldehyde and an amine R³ NH₂. ##STR5## Thecompounds of Structure 7 can be prepared by reacting a compound ofStructure 3 with ammonia.

The intermediate compounds of Structure 2 where X is HS(CH₂)_(n) NH- canbe prepared by reacting a compound of Structure 2 (where X is a suitableleaving group displaceable by an amine) with an amine of formulaHS(CH₂)_(n) NH₂.

The compounds of Structure 1 block histamine H₂ -receptors; that is,they inhibit the biological actions of histamine which are not inhibitedby "antihistamines" such as mepyramine but are inhibited by burimamide.For example, they inhibit histamine stimulated secretion of gastric acidfrom the lumen-perfused stomachs of rats anaesthetised with urethane, atdoses of from 0.5 to 256 micromoles per kilogram intravenously. Theiractivity as histamine H₂ -receptor antagonists is also demonstrated bytheir ability to inhibit other actions of histamine which are notmediated by histamine H₁ -receptors. For example, they inhibit theactions of histamine on the isolated guinea pig atrium and isolated ratuterus. They inhibit the basal secretion of gastric acid and also thatstimulated by pentagastrin or by food. In a conventional test such asthe measurement of blood pressure in the anaesthetised cat, at doses offrom 0.5 to 256 micromoles per kilogram intravenously, they inhibit thevasodilator action of histamine. The potency of the compounds isillustrated by an effective dose producing 50% inhibition of gastricacid secretion in the anaesthetised rat and 50% inhibition ofhistamine-induced tachycardia in the isolated guinea pig atrium (lessthan 10⁻⁴ Molar).

The pharmaceutical compositions of this invention comprise apharmaceutical carrier and a compound of Structure 1 in the form of thefree base or in the form of a pharmaceutically acceptable addition salt.Such addition salts include those with hydrochloric, hydrobromic,hydriodic, sulphuric and maleic acids, and their salts can convenientlybe formed from the corresponding bases by standard procedures, forexample by reacting the base with an acid in a lower alkanol or by theuse of ion exchange resins to form the required salt either directlyfrom the base or from a different addition salt.

The pharmaceutical carrier employed can be solid or liquid. Examples ofsolid carriers are lactose, terra alba, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate and stearic acid. Examples of liquidcarriers are syrup, peanut oil, olive oil and water.

If a solid carrier is used, the compositions can be prepared in the formof a tablet, capsule, troche or lozenge. The amount of solid carrier ina unit dosage form will generally be from about 25 mg to about 300 mg.If a liquid carrier is used, the compositions can be in the form of asyrup, emulsion, soft gelatin capsule, a sterile injectable liquid forexample contained in an ampoule, or an aqueous or non-aqueous liquidsuspension. The pharmaceutical compositions can be prepared byconventional techniques involving procedures such as mixing, granulatingand compressing or dissolving the ingredients as appropriate to thedesired form of composition.

The compositions of the present invention are preferably in dosage unitform each dosage unit containing an effective amount of activeingredient to block histamine H₂ -receptors. Each dosage unit preferablycontains the active ingredient in an amount of from about 50 mg to about250 mg.

The invention provides a method of blocking histamine H₂ -receptorswhich comprises administering to a subject an effective amount of acompound of Structure 1.

The active ingredient is preferably administered from one to six timesper day. The daily dosage regimen will generally be from about 150 mg toabout 1500 mg.

The route of administration can be oral or parenteral.

The invention is illustrated by the following Examples in whichtemperatures are in °C.

EXAMPLE 1

(a) A solution of sodium (0.09 g, 0.004 mol) in methanol (10 ml) wasadded dropwise to a stirred solution of1-nitro-2-methylthio-2-methylsulphinyl-ethylene (0.5 g, 0.003 mol) and3-bromopropylamine hydrobromide (0.9 g, 0.004 mol) in methanol (30 ml).The mixture was stirred for 5 hours, and then the solvent was removed invacuo. The residue was dissolved in water (20 ml) and extracted withchloroform (2×30 ml). The extracts were combined, dried, andconcentrated in vacuo. The solid residue was recrystallised frompropan-2-ol to give 1-nitro-2-methylthio-2-(3-bromopropylamino)ethylene(0.3 g, 43%) m.p. 92°-92.5°.

Found: C, 28.2; H, 4.3; N, 10.9; S, 12.5; Br, 31.3; C₆ H₁₁ Br N₂ O₂ S.Requires: C, 28.2; H, 4.35; N, 11.0; S, 12.6; Br, 31.3%.

(b) A mixture of 1-nitro-2-methylthio-2-(3-bromo-propylamino)ethylene(3.2 g, 0.012 mol) and sodium hydride (50% in oil, 0.9 g, 0.019 mol) indry tetrahydrofuran (50 ml) was refluxed for 18 hours. The mixture wasfiltered, and the filtrate was evaporated to dryness. The residue waschromatographed on a silica gel column, the product being eluted withethyl acetate. Recrystallisation of the product frommethanol/propan-2-ol gave2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.6 g, 29%) m.p.230.5°-231.5°.

Found: C, 41.5; H, 5.7; N, 16.1; S, 18.25; C₆ H₁₀ N₂ O₂ S. Requires: C,41.4; H, 5.8; N, 16.1; S, 18.4%.

(c) A solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.51 g,0.003 mol) and 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.49 g,0.003 mol) in ethanol (50 ml) was refluxed for 6 hours. The mixture wascooled, and the solvent was removed in vacuo. The residue was dissolvedin hot propan-2-ol and the product crystallised on cooling.Recrystallisation of the product from propan-2-ol/methanol gave2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-1,4,5,6-tetrahydropyridine(0.66 g, 82%) m.p. 205.5°-206.5°.

Found: C, 48.6; H, 6.5; N, 23.6; S, 10.8; C₁₂ H₁₉ N₅ O₂ S. Requires: C,48.5; H, 6.4; N, 23.55; S, 10.8%.

EXAMPLE 2

(a)(i) A solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (2g, 0.011 mol) and aziridine (0.5 g, 0.0116 mol) in methanol (20 mol) wasstirred at room temperature for 1 hour. The solid which crystallised outwas filtered off to give 1-nitro-2-methylthio-2-aziridnoethylene (1.3 g,74%) m.p. 107.5°-110°. ¹ H NMR (CDCl₃) δ:2.4 (S,4H, --H₂ CH₂ --), 2.56(S, 3H, CH₃ --) 7.15 ##STR6##

(a)(ii) Nitrogen was passed for about 15 minutes through a solution of1-nitro-2-methylthio-2-aziridino-ethylene (0.5 g, 0.003 mol) in dryacetone (15 ml) and the solution was then warmed to 35°. Potassiumiodide (2.5 g, 0.015 mol) was added to the solution, which resulted inthe rapid formation of a heavy yellow precipitate. The solid wasfiltered off, washed with water and then with acetone to give2-methylthio-3-nitro-4,5-dihydropyrrole (0.17 g, 34%) m.p. 207°-209°.

Found: C, 37.3; H, 4.9; N, 17.3; S, 19.75; C₅ H₈ N₂ O₂ S. Requires: C,37.5; H, 5.0; N, 17.5; S, 20.0%.

(b)(i) A solution of sodium methoxide (sodium (0.3 g, 0.013 mol) inmethanol (10 ml)) was added dropwise, over a period of 10 minutes to astirred mixture of 1-nitro-2-methylthio-2-methylsulphinylethylene (2 g,0.011 mol) and 2-bromoethylamine hydrobromide (2.7 g, 0.013 mol) inmethanol (25 ml), cooled to 0°. The solution was stirred at 0° for afurther 15 minutes, and then it was allowed to attain room temperature.After 1 hour, the solvent was removed in vacuo, and the semi-solidresidue was extracted with hot chloroform (2×25 ml). The extracts werecombined and concentrated in vacuo. The solid residue was recrystallisedfrom propan-2-ol to give1-nitro-2-methylthio-2-(2-bromo-ethylamino)ethylene (1.85 g, 71%) m.p.123°14 126°.

Found: C, 25.1; H, 3.7; N, 11.8; S, 13.6; Br, 33.3; C₅ H₉ BrN₂ O₂ S.Requires: C, 24.9; H, 3.8; N, 11.6; S, 13.3; Br, 33.1%.

(b)(ii) A solution of 1-nitro-2-methylthio-2-(2-bromoethylamino)ethylene(3 g, 0.012 mol) and sodium hydride (50% in oil, 0.62 g, 0.013 mol) indry tetrahydrofuran (100 ml) was refluxed for 7 hours. The reactionmixture was cooled, and the solvent was removed in vacuo. The residuewas extracted with boiling ethyl acetate (2×50 ml), and the extractswere decolourized with charcoal. Concentration of the extracts in vacuo,followed by cooling, resulted in the crystallisation of2-methylthio-3-nitro-4,5-dihydropyrrole (0.5 g, 26%).

(c) A solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.3 g,0.0076 mol) and 2-methylthio-3-nitro-4,5-dihydropyrrole (1.2 g, 0.0075mol) in ethanol (50 ml) was refluxed for 11/2hours. The mixture wascooled, and the solid was filtered off and recrystallised frommethanol/water to give2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole(1.4 g, 66%) m.p. 207.5°-208°.

Found: C, 46.65; H, 6.15; N, 24.6; S, 11.5; C₁₁ H₁₇ N₅ 0₂ S. Requires:C, 46.6; H, 6.05; N, 24.7; S, 11.3%.

EXAMPLE 3

(i) Aqueous ammonia (30% w/w, 9 ml, 0.16 mol) was added dropwise to asolution of 1-nitro-2-methylsulphinyl-2-methylthioethylene (20 g, 0.11mol) in tetrahydrofuran (80 ml) at 50°. The mixture was stirred at 50°for 1 hour. The solvent was removed in vacuo, and the residue waschromatographed on a silica gel column. The product was eluted withpetroleum ether (b.p. 60°-80°)/ethyl acetate (10:3) and recrystallisedfrom ethyl acetate-petroleum ether to give1-nitro-2-amino-2-methylthioethylene (1.5 g, 10%) m.p. 109°-110.5°.

Found: C, 27.1; H, 4.5; N, 20.7; S, 23.7; C₃ H₆ N₂ O₂ S. Requires: C,26.9; H, 4.5; N, 20.9; S, 23.9%.

(ii) Formaldehyde (40% w/v, 2 ml, 0.03 mol) and benzylamine (3 ml, 0.03mol) were successively added to a stirred solution of1-nitro-2-amino-2-methylthioethylene (1 g, 0.007 mol) in methanol (20ml). After 5 minutes, the solid was filtered off and recrystallised frommethanol to give1-benzyl-4-methylthio-5-nitro-1,2,3,6-tetrahydropyrimidine (1.3 g, 70%)m.p. 173°-173.5° C.

Found: C, 54.0; H, 5.6; N, 15.8; S, 11.8; C₁₂ H₁₅ N₃ O₂ S. Requires: C,54.3; H, 5.7; N, 15.8; S, 12.1%.

(iii) A solution of 1-benzyl-4-methylthio-5-nitro-1,1,2,3,6-tetrahydropyrimidine (1 g, 0.004 mol) and2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.7 g, 0.004 mol) inmethanol (40 ml) was heated, with stirring, at 60° for 10 hours. Thesolvent was removed in vacuo, and the residue was chromatographed on asilica-gel column. Ethyl acetate/propan-2ol (30%) eulted the productwhich was recrystallised from methanol-propan-2-ol to give1-benzyl-4-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-nitro-1,2,3,6-tetrahydropyrimidine(0.5 g, 32%) m.p. 177°-180°.

Found: C, 55.5; H, 6.3; N, 21.4; S, 8.0; C₁₈ H₂₄ N₆ O₂ S. Requires: C,55.65; H, 6.2; N, 21.6; S, 8.25%.

EXAMPLES 4 to 27

Substitution of an equivalent amount of

(a) 2-(2-imidazolylmethylthio)ethylamine

(b) 2-(4-imidazolylmethylthio)ethylamine

(c) 2-(5-bromo-4-imidazolylmethylthio)ethylamine

(d) 2-(5-trifluoromethyl-4-imidazolylmethylthio)-ethylamine

(e) 2-(5-hydroxymethyl-4-imidazolylmethylthio)-ethylamine

(f) 2-(2-pyridylmethylthio)ethylamine

(g) 2-(3-methyl-2-pyridylmethylthio)ethylamine

(h) 2-(3-methoxy-2-pyridylmethylthio)ethylamine

(i) 2-(3-chloro-2-pyridylmethylthio)ethylamine

(j) 2-(3-amino-2-pyridylmethylthio)ethylamine

(k) 2-(3-hydroxy-2-pyridylmethylthio)ethylamine

(l) 2-(3-isothiazolylmethylthio)ethylamine

(m) 2-(4-bromo-3-isothiazolylmethylthio)ethylamine

(n) 2-(3-(1,2,5)-thiadiazolymethylthio)ethylamine

(o) 2-(4-chloro-3-(1,2,5)-thiadiazolylmethylthio)-ethylamine

(p) 2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio)-ethylamine

(q) 2-((5-(dimethylaminomethyl)2-furyl)methylthio)-ethylamine

(r) 2-((5-(methylaminomethyl)-2-furyl)methylthio)-ethylamine

(s) 2-((5-(1-pyrrolidinomethyl)-2-furyl)methylthio)-ethylamine

(t) 2-((5-(methylethylaminomethyl)-2-furyl)methylthio)ethylamino

(u) 2-((5-dimethylaminomethyl)2-thienyl)methylthio)ethylamine

(v) 2-((5-(methylaminomethyl)-2-thienyl)methylthio)ethylamine

(w) 2-((5-(1-pyrrolidinomethyl)-2-thienyl)methylthio)ethylamine

(x) 2-((5-(methylethylaminomethyl)-2-thienyl)methylthio)ethylamino

for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure ofExample 2 leads to the production of:

Example Number

4. 2-[2-(2-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

5. 2-[2-(4-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

6.2-[2-(5-bromo-4-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

7.2-[2-(5-trifluoromethyl-4-imidazolylmethylthio)-ethylamino]-3-nitro-4,5-dihydropyrrole

8.2-[2-(5-hydroxymethyl-4-imidazolylmethylthio)-ethylamino]-3-nitro-4,5-dihydropyrrole

9. 2-[2-(2-pyridylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

10.2-[2-(3-methyl-2-pyridylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

11.2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

12.2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

13.2-[2-(3-amino-2-pyridylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

14.2-[2-(3-hydroxy-2-pyridylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

15.2-[2-(3-isothiazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

16.2-[2-(4-bromo-3-isothiazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

17.2-[2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

18.2-[2-(chloro-3-(1,2,5)-thiadiazolylmethylthio)-ethylamino]-3-nitro-4,5-dihydropyrrole

19.2-[2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio)-ethylamino]-3-nitro-4,5-dihydropyrrole

20.2-[2-(5-(dimethylaminomethyl)-2-furylmethylthio)-ethylamino]-3-nitro-4,5-dihydropyrrole

21.2-[2-(5-(methylaminomethyl)-2-furylmethylthio)-ethylamino]-3-nitro-4,5-dihydropyrrole22.2-[2-(5-(1-pyrrolidinomethyl)-2-furylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

23.2-[2-(5-(methylethylaminomethyl)-2-furylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

24.2-[2-(5-(dimethylaminomethyl)-2-thienylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

25.2-[2-(5-(methylaminomethyl)-2-thienylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

26.2-[2-(5-(1-pyrrolidinomethyl)-2-thienylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

27.2-[2-(5-(methylethylaminomethyl)-2-thienylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole

Substitution of equivalent amounts of the above specified amines for2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedures ofExample 1 and Example 3 leads to the production of the corresponding2-[2-heterocyclylmethylthio)-ethylamino]-3-nitro-1,4,5,6-tetrahydropyridinesand1-benzyl-4-[2-(heterocyclylmethylthio)ethylamino]-5-nitro-1,2,3,6-tetrahydropyrimidinesrespectively.

EXAMPLES 28 to 31

Substitution of an equivalent amount of

(a) 4-(3-thiazolyl)butylamine,

(b) 4-(3-oxazolyl)butylamine,

(c) 4-(2-isoxazolyl)butylamine,

(d) 4-[3-(1,2,4-triazolyl)]butylamine,

for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure ofExample 2 leads to the production of

Example Number

28. 2-[4-(3-thiazolyl)butylamino]-3-nitro-4,5-dihydropyrrole

29. 2-[4-(3-oxazolyl)butylamino]-3-nitro-4,5-dihydropyrrole

30. 2-[4-(2-isoxazolyl)butylamino]-3-nitrodihydropyrrole

31. 2-[4-(3-(1,2,4-triazolyl)butylamino]-3-nitrodihydropyrrole

EXAMPLE 32

Acid addition salts of the compounds of Examples 1 to 31 are prepared byreaction of the respective free bases with an appropriate acid. Thehydrochlorides are prepared by reaction with hydrochloric acid, thereaction being effected in ethanol solution.

EXAMPLE 33

A pharmaceutical composition is prepared from the following ingredients:

    ______________________________________                                        2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-                          nitro-1,4,5,6-tetrahydropyridine                                                                         150 mg                                             Sucrose                     75 mg                                             Starch                      25 mg                                             Talc                        5 mg                                              Stearic Acid                2 mg                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

The other compounds of Structure 1 can be formulated into pharmaceuticalcompositions in a similar manner, and these compositions areadministered to a subject within the dose ranges given above to blockhistamine H₂ -receptors.

We claim:
 1. A compound represented by Structure 1: ##STR7## in whichHet is imidazole or pyridine which is attached at a ring carbon andwhich is optionally substituted by lower alkyl, trifluoromethyl,hydroxymethyl, halogen, hydroxy, lower alkoxy, or amino, provided thatwhen Het is imidazole, the optional substituents do not include hydroxyor amino;Z is sulphur, methylene or oxygen; m is 0, 1 or 2 and n is 2 or3 provided that m+n is 3 or 4; and B is a 1,2-ethanediyl (--CH₂ --CH₂--) or 1,3-propanediyl (--CH₂ CH₂ CH₂ --) group, which group isoptionally substituted with one lower alkyl, aryl, aryl lower alkyl orheteroaryl lower alkyl group, aryl being phenyl optionally substitutedby lower alkyl, lower alkoxy or halogen and heteroaryl being 2-furyl,2-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl optionally substituted bylower alkyl or lower alkoxy, or a pharmaceutically acceptable acidsolution salt thereof.
 2. A compound according to claim 1, where(CH₂)_(m) is linked to a carbon atom of the heterocycle Het adjacent toa nitrogen atom thereof.
 3. A compound according to claim 1, where Hetis 2- or 4-imidazolyl optionally substituted by lower alkyl, halogen,trifluoromethyl or hydroxymethyl; or 2-pyridyl optionally substituted bylower alkyl, lower alkoxy, halogen, amino or hydroxy.
 4. A compoundaccording to claim 3, where Het is 2- or 4-imidazolyl optionallysubstituted by methyl, chlorine or bromine; or 2-pyridyl optionallysubstituted by methyl, methoxy, chlorine or bromine.
 5. A compoundaccording to claim 1, where Het is 5-methyl-4-imidazolyl,5-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl,3-methoxy-2-pyridyl and 3-hydroxy-2-pyridyl.
 6. A compound according toclaim 1, which is2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-1,4,5,6-tetrahydropyridineor a pharmaceutically acceptable acid addition salt thereof.
 7. Acompound according to claim 1, which is2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrroleor a pharmaceutically acceptable acid addition salt thereof.
 8. Apharmaceutical composition to block histamine H₂ -receptors comprising,in an effective amount to block said receptors, a compound according toclaim 1 and a pharmaceutical carrier.
 9. A method of blocking histamineH₂ -receptors which comprises administering an effective amount of acompound according to claim 1 to an animal in need of such treatment.